bims-lypmec 2023-08-20 papers

Nat Cell Biol. 2023 Aug 14.

Balancing lysosome abundance in health and disease.

Anders P Mutvei, Michal J Nagiec, John Blenis.

Lysosomes are catabolic organelles that govern numerous cellular processes, including macromolecule degradation, nutrient signalling and ion homeostasis. Aberrant changes in lysosome abundance are implicated in human diseases. Here we outline the mechanisms of lysosome biogenesis and turnover, and discuss how changes in the lysosome pool impact physiological and pathophysiological processes.

DOI: https://doi.org/10.1038/s41556-023-01197-7

Curr Biol. 2023 Aug 10. pii: S0960-9822(23)00970-3. [Epub ahead of print]

Optineurin tunes outside-in signaling to regulate lysosome biogenesis and phagocytic clearance in the retina.

Li Xuan Tan, Colin J Germer, Thushara Thamban, Nilsa La Cunza, Aparna Lakkaraju.

Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) are essential for healthy vision. Disrupted autophagy due to mechanistic target of rapamycin (mTOR) overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting light chain 3 (LC3), which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, transient receptor potential-mucolipin 1 (TRPML1)-dependent manner. RNA-seq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard the metabolic fitness of the RPE throughout the organismal lifespan.

Keywords: TFEB; TRPML1; lysosomes; macular degeneration; phagocytosis; photoreceptors; retinal pigment epithelium; trogocytosis

DOI: https://doi.org/10.1016/j.cub.2023.07.031

Nat Aging. 2023 Aug 14.

Tubular lysosome induction couples animal starvation to healthy aging.

Tatiana V Villalobos, Bhaswati Ghosh, Kathryn R DeLeo, Sanaa Alam, Cristian Ricaurte-Perez, Andrew Wang, Brennan M Mercola, Tyler J Butsch, Cara D Ramos, Suman Das, Eric D Eymard, K Adam Bohnert, Alyssa E Johnson.

Dietary restriction promotes longevity in several species via autophagy activation. However, changes to lysosomes underlying this effect remain unclear. Here using the nematode Caenorhabditis elegans, we show that the induction of autophagic tubular lysosomes (TLs), which occurs upon dietary restriction or mechanistic target of rapamycin inhibition, is a critical event linking reduced food intake to lifespan extension. We find that starvation induces TLs not only in affected individuals but also in well-fed descendants, and the presence of gut TLs in well-fed progeny is predictive of enhanced lifespan. Furthermore, we demonstrate that expression of Drosophila small VCP-interacting protein, a TL activator in flies, artificially induces TLs in well-fed worms and improves C. elegans health in old age. These findings identify TLs as a new class of lysosomes that couples starvation to healthy aging.

DOI: https://doi.org/10.1038/s43587-023-00470-6

Methods Mol Biol. 2023 ;2712 91-102

Monitoring Lysosome Function in Ferroptosis.

Fangquan Chen, Rui Kang, Daolin Tang, Jiao Liu.

Ferroptosis is a type of regulated cell death that occurs due to iron-induced membrane lipid peroxidation. Lysosomes, which are acidic, membrane-bound organelles containing various hydrolases, play a vital role in ferroptosis. They not only aid in the degradation of autophagic substrates, but also serve as signaling hubs in cell death. Specifically, lysosomes are involved in the induction and execution of ferroptosis through autophagy-mediated degradation of anti-ferroptotic proteins, lysosomal membrane permeability-mediated release of cathepsins, and iron-induced lysosomal membrane lipid peroxidation. Therefore, it is essential to have reliable methods for monitoring lysosomal functions, including lysosomal activity, pH, and membrane integrity, as well as iron accumulation and lipid peroxidation, to understand ferroptosis. This chapter introduces several protocols, such as western blotting, immunofluorescence, lysosomal probes, and lipid peroxidation assay kits, for monitoring the process of lysosome-related ferroptosis.

Keywords: Autophagy; Cell death; Ferroptosis; Lysosome

DOI: https://doi.org/10.1007/978-1-0716-3433-2_9

Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00559-2. [Epub ahead of print]83(16): 2832-2833

A sweet way to regulate cellular growth: OGT and mTOR join forces.

Pedro Latorre-Muro, Pere Puigserver.

In this issue, Xu and Pan et al1 report a glucose-sensing and activation mechanism of mTORC1 through the glycosyltransferase OGT, which activates Raptor, allowing lysosomal targeting of mTORC1 to promote cell proliferation.

DOI: https://doi.org/10.1016/j.molcel.2023.07.016